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      The whole-genome landscape of medulloblastoma subtypes

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 1 , 10 , 11 , 11 , 11 , 2 , 12 , 8 , 13 , 14 , 3 , 11 , 1 , 11 , 1 , 10 , 1 , 10 , 1 , 10 , 7 , 3 , 1 , 10 , 4 , 3 , 15 , 3 , 16 , 3 , 5 , 3 , 15 , 3 , 15 , 3 , 4 , 3 , 3 , 5 , 17 , 12 , 12 , 8 , 7 , 18 , 19 , 20 , 20 , 20 , 20 , 6 , 6 , 6 , 6 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 33 , 33 , 33 , 33 , 33 , 33 , 33 , 33 , 17 , 17 , 34 , 34 , 34 , 12 , 13 , 19 , 20 , 14 , 9 , 11 , 3 , 4 , 10 , 3 , 3 , 5 , 10 , 33 , 1 , 10 , 17 , , 6 , 35 , , 7 , 10 ,
      Nature
      Nature Publishing Group UK
      Cancer genomics, CNS cancer

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          Abstract

          Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and ‘enhancer hijacking’ events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

          Supplementary information

          The online version of this article (doi:10.1038/nature22973) contains supplementary material, which is available to authorized users.

          Abstract

          Genomic analysis of 491 medulloblastoma samples, including methylation profiling of 1,256 cases, effectively assigns candidate drivers to most tumours across all molecular subgroups.

          Supplementary information

          The online version of this article (doi:10.1038/nature22973) contains supplementary material, which is available to authorized users.

          Genomic landscapes of medulloblastomas

          Medulloblastomas are highly malignant brain tumours that develop during childhood. Paul Northcott and colleagues analysed the whole-genome sequences of 491 medulloblastomas in order to characterize the genomic landscape across tumours and identify new drivers and mutational signatures. Their integrative genomic analyses, including methylation profiling of 1,256 medulloblastomas, identifies subgroup-specific driver mutations and suggests additional tumour subtypes. The authors assign driver mutations to a high proportion of the less well characterized Group 3 and Group 4, which together contribute to more than 60% of all medulloblastomas.

          Supplementary information

          The online version of this article (doi:10.1038/nature22973) contains supplementary material, which is available to authorized users.

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          Most cited references17

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          Integration of biological networks and gene expression data using Cytoscape.

          Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.
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            Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

            Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. Copyright © 2012 Elsevier Inc. All rights reserved.
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              iRefIndex: A consolidated protein interaction database with provenance

              Background Interaction data for a given protein may be spread across multiple databases. We set out to create a unifying index that would facilitate searching for these data and that would group together redundant interaction data while recording the methods used to perform this grouping. Results We present a method to generate a key for a protein interaction record and a key for each participant protein. These keys may be generated by anyone using only the primary sequence of the proteins, their taxonomy identifiers and the Secure Hash Algorithm. Two interaction records will have identical keys if they refer to the same set of identical protein sequences and taxonomy identifiers. We define records with identical keys as a redundant group. Our method required that we map protein database references found in interaction records to current protein sequence records. Operations performed during this mapping are described by a mapping score that may provide valuable feedback to source interaction databases on problematic references that are malformed, deprecated, ambiguous or unfound. Keys for protein participants allow for retrieval of interaction information independent of the protein references used in the original records. Conclusion We have applied our method to protein interaction records from BIND, BioGrid, DIP, HPRD, IntAct, MINT, MPact, MPPI and OPHID. The resulting interaction reference index is provided in PSI-MITAB 2.5 format at . This index may form the basis of alternative redundant groupings based on gene identifiers or near sequence identity groupings.
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                Author and article information

                Contributors
                s.pfister@dkfz-heidelberg.de
                mdtaylor@sickkids.ca
                peter.lichter@dkfz-heidelberg.de
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                20 July 2017
                20 July 2017
                2017
                : 547
                : 7663
                : 311-317
                Affiliations
                [1 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Pediatric Neurooncology, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [2 ]GRID grid.240871.8, ISNI 0000 0001 0224 711X, Department of Developmental Neurobiology, , St Jude Children’s Research Hospital, ; Memphis, Tennessee USA
                [3 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Theoretical Bioinformatics, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [4 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Applied Bioinformatics, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [5 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Department for Bioinformatics and Functional Genomics, , Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, ; Heidelberg, Germany
                [6 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, ; Toronto, Ontario
                [7 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Molecular Genetics, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [8 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory, ; Rigshospitalet, Denmark
                [9 ]GRID grid.116068.8, ISNI 0000 0001 2341 2786, Department of Biological Engineering, , Massachusetts Institute of Technology, ; Cambridge, Massachusetts USA
                [10 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, German Cancer Consortium (DKTK), ; Heidelberg, Germany
                [11 ]GRID grid.4709.a, ISNI 0000 0004 0495 846X, Genome Biology Unit, European Molecular Biology Laboratory (EMBL), ; Heidelberg, Germany
                [12 ]GRID grid.419538.2, ISNI 0000 0000 9071 0620, Department of Vertebrate Genomics, , Max Planck Institute for Molecular Genetics, ; Berlin, Germany
                [13 ]GRID grid.240871.8, ISNI 0000 0001 0224 711X, Department of Structural Biology, , St Jude Children’s Research Hospital, ; Memphis, Tennessee USA
                [14 ]GRID grid.66859.34, Broad Institute of Harvard and MIT, ; Cambridge, Massachusetts USA
                [15 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [16 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Medical Faculty Heidelberg, Heidelberg University, ; Heidelberg, Germany
                [17 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Department of Pediatric Hematology and Oncology, , Heidelberg University Hospital, ; Heidelberg, Germany
                [18 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [19 ]GRID grid.240871.8, ISNI 0000 0001 0224 711X, Department of Oncology, , St Jude Children’s Research Hospital, ; Memphis, Tennessee USA
                [20 ]GRID grid.240871.8, ISNI 0000 0001 0224 711X, Department of Computational Biology, , St Jude Children’s Research Hospital, ; Memphis, Tennessee USA
                [21 ]GRID grid.5650.6, ISNI 0000000404654431, Department of Oncogenomics, , Amsterdam Medical Center, ; Amsterdam, Netherlands
                [22 ]GRID grid.418542.e, ISNI 0000 0000 6686 1816, Department of Neuropathology, , NN Burdenko Neurosurgical Institute, ; Moscow, Russia
                [23 ]GRID grid.5288.7, ISNI 0000 0000 9758 5690, Department of Pediatrics, , Papé Family Pediatric Research Institute, Knight Cancer Institute, Oregon Health and Science University, ; Portland, Oregon USA
                [24 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Neurology, , Boston Children's Hospital and Harvard Medical School, ; Boston Massachusetts USA
                [25 ]Department of Neurosurgery, University Clinic, Heidelberg University, Heidelberg Hospital, Germany
                [26 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Department of Neurosurgery, , University Hospital Tübingen, ; Tübingen, Germany
                [27 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Department of Hematology and Oncology, , Children’s University Hospital Tübingen, ; Tübingen, Germany
                [28 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Neurosurgery, , David Geffen School of Medicine at UCLA, ; Los Angeles, California USA
                [29 ]GRID grid.411160.3, ISNI 0000 0001 0663 8628, Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, ; Barcelona, Spain
                [30 ]GRID grid.26009.3d, ISNI 0000 0004 1936 7961, Department of Pathology, , Duke University, ; Durham, North County USA
                [31 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Department of Pediatrics, , McGill University, ; Montreal, Quebec Canada
                [32 ]GRID grid.410786.c, ISNI 0000 0000 9206 2938, Department of Neurosurgery, , Kitasato University School of Medicine, ; Sagamihara, Japan
                [33 ]GRID grid.248762.d, ISNI 0000 0001 0702 3000, Michael Smith Genome Sciences Centre, BC Cancer Agency, ; Vancouver, British Columbia Canada
                [34 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Department of Neuropathology, , Heidelberg University Hospital, ; Heidelberg, Germany
                [35 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Division of Neurosurgery, , Hospital for Sick Children, ; Toronto, Ontario Canada
                Article
                BFnature22973
                10.1038/nature22973
                5905700
                28726821
                ec9e3096-04df-4b9b-b9c3-32f843666ac4
                © The Author(s) 2017

                This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 22 September 2016
                : 10 May 2017
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                © Springer Nature Limited 2017

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                cancer genomics,cns cancer
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                cancer genomics, cns cancer

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